The weaver GIRK2 mutation leads to decreased levels of serum thyroid hormone: Characterization of the effect on midbrain dopaminergic neuron survival

The selective neurodegenerative changes occurring in the weaver mutant cere bellum and midbrain are Linked to a point mutation in an inward rectifying potassium channel (GIRK2). However, given that GIRK2 is widely expressed in the CNS, it is not understood why this mutation only leads to neuroanatomi cally selective and developmentally specific neuronal cell death. Here we s how that the phenotype of the weaver mutant mouse includes hypothyroidism, which is associated with delays in somatic development and decreased expres sion of striatal transforming growth factor alpha (TGF-alpha). Since thyroi d hormone has major effects on brain development, further studies were perf ormed to address whether some of pathological changes detected the weaver m utant mouse are due to the reduced thyroid hormone levels. We observed that daily thyroid hormone replacement was able to stimulate somatic growth and restore TGF-alpha expression to wild-type levels, indicating that while th ese mice are responsive to thyroid hormone they possibly have a defect in t he ability to regulate its release at the level of the hypothalamic pituita ry axis. However when we assessed whether thyroid hormone replacement could rescue midbrain dopaminergic neurons we found that this treatment accelera ted rather than attenuated neurodegeneration. We did not observe that thyro id hormone was able to directly regulate expression of GIRK2 mRNA levels in the midbrain and therefore, speculate that the mechanism by which thyroid hormone accelerates midbrain dopaminergic neurodegeneration is by enhancing the maturation of the striatonigral inputs. In summary, we detected reduce d levels of serum thyroid hormone in the weaver mutant mouse, which appears to be responsible for delays in somatic growth and the onset of neurodegen erative changes in the midbrain. (C) 1999 Academic Press.